The invention relates to a device for inhaling dosed pharmaceuticals in the form of an aerosol into the lungs. Suitable pharmaceuticals include analgesics, anti-angina agents, anti-allergics, antihistamines and anti-inflammatory agents, expectorants, antitussives, bronchodilators, diuretics, anticholinergics, corticoids, xanthins, anticancer drugs and therapeutically active proteins or peptides, such as insulin or interferon.
The administration of pharmaceuticals including vitamin A is particularly useful for treating respiratory diseases, such as asthma, and for the prophylactic treatment and therapy of the mucosae of the tracheobronchial tract.
The term xe2x80x9cvitamin Axe2x80x9d stands for a number of chemically similar compounds producing different effects in human and animal organisms. Vitamin A is essential for man as a vitamin deficiency appears if the vitamin is not supplied together with food. A vitamin A deficiency shows up in various modifications in the skin, mucosae and eyes. Symptoms include a cornification (keratinisation) of the mucosae of the respiratory system or the connective tissue membrane of the eye and a higher disposition for infections and blindness, where the deficiency is pronounced. The majority of the modifications resulting from the deficiency, especially in the mucosae, can be repaired by a vitamin A supply. However, the systemic administration aiming at the repair, of for instance a pavement (squamous) epithelium metaplasia, or at the prevention of a recurrence of such modifications requires high concentrations, which can sometimes produce considerable side effects (cerebral pressure symptoms, disorders of the liver cell metabolism, etc.). Moreover, the use of preparations in high doses is contraindicated in pregnancy because of the risks of fetal deformation (Bauernfeind J. C.: The Safe Use of Vitamin A, The Nutrition Foundation, Washington D.C., 1980).
Moreover, in the case of a diet-caused protein deficiency and in the case of disorders of the liver cell metabolism, such as inflammation or cirrhosis, the supply of vitamin A even in physiological concentrations is banned, because the associated disorders of protein synthesis (deficient formation of the transport proteins) of the liver do not allow the vitamin to be eliminated from the storage organs into which it is transferred after resorption (absorption).
Furthermore, after systemic administration, the vitamin can only be taken up by the peripheral target tissues, such as the respiratory epithelium, and caused to exert its function, if it is bound to this very transport protein.
EP-A-0 352 412 describes the use of a preparation of esters of retinol and retinoic acid for administration by inhalation to solve this problem. This in particular allows the active ingredient to exert a topical action on the mucosae of the tracheobronchial tract of man and animal. This facilitates the prophylactic treatment and therapy of specific diseases and functional abnormalities, for instance of specific cellular differentiation disorders, pavement (squamous) epithelium metaplasia, neoplastic modifications, reduced activity of the ciliated epithelium and dysfunction of mucosa-forming cells. Moreover, this preparation can also be used for the therapy or as an adjuvant in the therapy of inter alia bronchial carcinoma, acute and chronic bronchites and the bronchopulmonary dysplasia of newborn children. Clinical studies reveal, however, that the application of vitamin A by inhalation using conventional inhalators only allows insufficient amounts of the active ingredient to be administered to the target tissue, the ciliated epithelium of the bronchial mucosa.
DE-A-199 12 461 by the same inventors as those named for the present patent application was published on Sep. 21, 2000 and is consequently a postpublished document. It discloses a device for limiting the flow at low differential pressures, in particular for limiting the inhalation flow volume during the inhalation of therapeutic aerosols. The device has a housing which comprises an inhalation opening, an exhalation opening, and a flow channel arranged therebetween and has a flat oblong cross section and flexible large-surface walls. Depending on the differential pressure between the inhalation opening and the exhalation opening and the flexibility of the wall material, the cross section of the flow channel can be reduced in size to suit a predetermined maximum inhalation flow volume.
Essentially, the administration of pharmaceuticals in the form of an aerosol to the lung by inhalation is influenced by four factors: (i) the particle size and particle properties of the aerosol; (ii) the volume inhaled by the patient in one breath; (iii) the patient""s breath flow; and (iv) the patient""s morphometry and respiratory system. Although aerosols in suitable particle size ranges are produced by the conventional systems, the parameters xe2x80x9cone breath volumexe2x80x9d and xe2x80x9cbreath flowxe2x80x9d (rate of breathing) are taken into account either insufficiently or not at all. This leads to an uncontrolled inhalation of the aerosol, which in turn has the result that the aerosol particles reach the lung in insufficient amounts or do not reach the areas (for instance the alveolar area) within the lung to be treated.
EP-A 0 965 355 proposes a device for the controlled application of a measured amount of pharmaceuticals into the lung by inhalation. This controlled inhalator comprises a closed container which can be filled with a predetermined aerosol volume and from which the aerosol can be withdrawn via a control means for the inhalation flow. In this known inhalator, said control means is either an adjustable valve or a critical nozzle. The use of an adjustable valve or a critical nozzle allows the breath flow to be limited.
EP-B-0 050 654 proposes an inhalation device for the administration of pulmonary medication. This device has an inflatable envelope from which an aerosol can be inhaled through a mouthpiece. This aerosol is introduced via a nebulizer into the inflatable envelope from a cartridge prior to inhalation. In order to limit the amount of air flowing through the mouthpiece during inhalation, the mouthpiece has a restriction. This restriction limits the breath flow during inhalation.
The two above-mentioned inhalation devices are distinguished by the fact that the flow is limited, i.e. during the inspiratory phase, the breath flow rises only slowly and the breath flow increase decreases steadily, leading to a steady flattening of the curve in the graph of the breath flow versus time. The result of this flow limitation is that, depending on the patient""s inspiratory capacity, the breath flow increases differently (and flattens) and, in the worst case, is insufficient for the treatment required. This means that the envisaged flow limitation of the known inhalators can lead to an insufficient aerosol deposition.
In light of this, the invention addresses the problem of providing an inhalation device, which, irrespective of the patient""s characteristics, provides the breath flow required for the inhalation of aerosols, in particular vitamin A. This problem is solved by an inhalation device possessing the features of the claims.
The invention starts from the basic idea of providing a control means which keeps the inhalation flow at an essentially constant level during the entire inhalation period of the aerosol. This means that according to the invention, the inhalation flow increases right at the start of the inspiratory phase to its maximum value, which is required for adequate aerosol administration, and remains at this maximum value as long as the patient produces a minimum pressure during inhalation. This minimum pressure is preferably 10 mbar at the most and preferably lies in the range between 5 and 10 mbar. According to the invention, a flow limitation is thus provided even at low differential pressures.
The inhalation device according to the invention is a combination of a self-expanding container for a predetermined aerosol volume, a means for introducing aerosol from an aerosol dispenser into the container and a means for controlling the inhalation flow, the control means keeping the inhalation flow at an essentially constant level during the entire inhalation period.
According to the invention, the control means has a flow channel comprising an inlet opening and an outlet opening, which are spaced apart from each other and arranged at the two ends of the flow channel.
According to a first embodiment, the flow channel is formed by a flexible large-surface wall and an essentially stiff wall arranged in parallel thereto. The flexible wall is covered by a cover at the side facing away from the flow channel. The outlet opening of the flow channel preferably leads into the interior of a housing surrounding the aerosol container. Prior to being inhaled, the aerosol is introduced into the interior of the container, for instance from a cartridge, preferably via a nozzle, such as a nebulizer. In the course of this, the container expands until its interior, in the completely expanded state of the container, is filled with an aerosol volume predetermined by the volume of the container. As soon as a patient inspires the aerosol from the container via a mouthpiece, which is preferably provided, the container draws together because of the suction effect. The negative pressure forming in the interior of the container in consequence of this is compensated for by the flow channel. The negative pressure acting on it has the result that, depending on the degree of the negative pressure, the flexible wall bulges towards the interior of the flow channel and in this manner reduces its cross section. This reduction of the cross section results in a limitation of the air flow through the flow channel into the interior of the housing for pressure compensation, which in turn limits the aerosol flow from the container. Due to the control means of the invention, an automatic volume flow regulation of the flow channel, and thus an automatic breath flow regulation, is brought about at pressures as low as 5 mbar. The negative pressure formed during the inhalation of the aerosol results in a direct reduction of the cross section of the flow channel because of the flexible wall, i.e., in a direct reduction to a limit value. As a consequence of this, the breath flow limit value is achieved right at the start of inhalation and is maintained during the entire inhalation period at pressures of 80 to 100 mbar, as normally produced by the inspiration of the lung.
In a preferred embodiment, the essentially stiff wall of the flow channel has one or more oblong depressions or grooves which extend in the direction of the channel and are spaced apart from each other by corresponding ribs or ribs. The flexible wall, which preferably consists of a bio-compatible material such as silicone or rubber, bulges into the depressions during inhalation and rests on the ribs. The ribs prevent the flow channel from closing completely and limit the reduction of the channel""s cross section.
According to an alternative embodiment, the flow channel is delimited by two flexible walls arranged in parallel and spaced apart from each other, which, depending on the negative pressure, bend towards the inside and thus reduce the cross section of the channel.
In a third embodiment, the control means is provided in the form of a cylindrical housing, with a circular flow channel being formed in the interior of this housing by two flexible cylindrical walls.
According to a fourth embodiment, the inhalation device of the invention possesses not only the self-expandable container and the introduction means for the aerosol but also a control means that comprises several flow channels which form a star and are situated between the ribs extending in the form of a star. These ribs support a circular flexible mat which, upon generation of a negative pressure in the flow channels, bulges into the flow channels as in the first embodiment and reduces the cross section, thus adjusting the flow volume to an essentially constant value. The ribs are either of the same length or at least one web is longer.
The means for introducing aerosol from an aerosol dispenser into the container prevents medication, such as vitamin A in the form of an aerosol, from being released directly from the aerosol dispenser into the mouth and inhaled. Rather, the patient is obligated to introduce the aerosol from the aerosol dispenser into the container and only then, with the use of the inhalation device of the invention, can the patient inhale the predetermined aerosol volume defined by the container. The aerosol dispenser, such as a cartridge, is preferably connected over a collar to a nozzle and is held at the inhalation device. The aerosol is then introduced into the interior of the container via the nozzle. Other preferred features are specified in the dependent claims.
The inhalation device preferred according to the invention has numerous advantages. The inhalation device permits uniform and precise dosing of the medication, irrespective of the patient""s coordination ability. Different volumina of the container allow the desired deposition site in the lung and also the desired amount of aerosol to be preselected. If the housing is at least in part made transparent, the inhaled volume can be visually controlled, as the patient sees the container folding up. The inhalation device is easy to handle and at the same time highly effective. With the introduction of the active ingredient into the container prior to inhalation, the aerosol release from the dispenser is limited to the necessary amount, thus preventing excessive consumption. The precise and efficient dosing in turn leads to low costs of treatment, for instance with vitamin A. Another advantage of the invention is the fact that the use of a propellant is not absolutely necessary, for instance for the administration of vitamin A.
The term xe2x80x9csuitable pharmaceuticalsxe2x80x9d as used herein, includes active ingredients, medicaments, compounds, compositions, or mixtures of substances bringing about a pharmacological, often advantageous, effect. It includes food, food supplements, nutrients, medicaments, vaccines, vitamins, and other useful active ingredients. Moreover, the terms, as used herein, include any physiologically or pharmacologically active substances, bringing about a topical or systemic effect in a patient. The active ingredient lending itself to administration in the form of an aerosol can be an antibody, antiviral active ingredient, anti-epileptic, analgesic, anti-inflammatory active ingredient, and bronchodilator or can be an organic or inorganic compound, which without any restrictions can also be a medicament having an effect on the peripheral nervous system, adrenergic receptors, cholinergic receptors, skeletal muscles, cardiovascular system, unstriated muscles, circulatory system, neuronal connections, endocrine and hormonic system, immune system, reproductive system, skeletal system, food supply system and excretory system, histamine cascade or central nervous system. Suitable active ingredients are for instance polysaccharides, steroids, hypnotics and sedatives, activators, tranquilizers, anticonvulsives (antispasmodics) and muscle-relaxants, anti-Parkinson-substances, analgesics, anti-inflammatory agents, antimicrobial active ingredients, antimalarial agents, hormones, including contraceptives, symphatocomimetics, polypeptides and proteins producing physiological effects, diuretics, substances regulating the lipometabolism, anti-androgenic active ingredients, antiparasitics, neoplastic and antineoplastic agents, antidiabetics, food and food supplements, growth-promoters, fats, stool-regulators, electrolytes, vaccines and diagnostics.
The invention is particularly suited for inhalation application of different active ingredients, such as the following ones (without being restricted thereto): Insulin, calcitonin, erythropoietin (EPO), factor VII, factor IX, cylcosporin, granulozyte colony stimulating factor (GCSF), alpha-1-proteinase inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormones, human growth hormone (HGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha, interferon beta, interferon gamma, interleukin-2, luteinizing hormone releasing hormone (LHRH), somatostatin, somatostatin-analogs, including octreotides, vasopressin analogs, follicle stimulating hormone (FSH), insulin-like growth factor, insulintropin, interleukin-I receptor antagonist, interleukin-3, interleukin-4, interleukin-6, macrophage colony stimulating factor (M-CSF), nerve growth factor, parathryoid hormone (PTH), thymosin alpha 1, IIb/IIIa inhibitor, alpha-1 antitrypsin, antibodies against respiratorily syncytic virus, cystic fibrosis transmembrane regulator gene (CFTR), desoxyribonuclease (Dnase), bactericides, permeability increasing protein (BPI), anti-CMV antibodies, interleukin-1-receptor, retinol, retinyl-ester, tocopherols and their esters, tocotrienols and their esters, carotinoids, in particular beta carotin and other natural and synthetic antioxidants, retinol acids, pentamides, albuterolsulfate, metaproterenolsulfate, beclomethasonedipropionate, triamcinolonacetamide, budesonidacetonides, ipratropium bromide, flunisolides, fluticasones, cromolyn potassium, ergotamine tartrate and the analogs, agonists and antagonists of the above-mentioned substances. Moreover, active ingredients can be nucleic acids in the form of pure nucleic acid molecules, viral vectors, associated viral particles, nucleic acids associated with or contained in lipids or a lipid-containing material, plasmid DNA or plasmid RNA or other constructs from nucleic acids, which are suitable for cell transfection or cell transformation, in particular in the case of cells of the alveolar region of the lung. The active ingredient can be present in different forms, such as soluble or insoluble, charged or uncharged molecules, components of molecular complexes or pharmacologically acceptable inactive ingredients. The active ingredient can consist of naturally occurring molecules or their recombinant products, or the molecules can be analogs of the naturally occurring or recombinantly produced active ingredients to which or from which one or more amino acids have been added or deleted. Moreover, the active ingredient can contain attenuated live vaccines or killed viruses for vaccination purposes. If the active ingredient is insulin, it includes naturally extracted human insulin, recombinant human insulin, insulin extracted from cattle and/or swine, recombinant porcine or bovine insulin and mixtures of the above-mentioned insulins. The insulin can be present in a purified, that is a substantially purified form, but can also contain usual commercial extracts. The term xe2x80x9cinsulinxe2x80x9d also includes analogs, to which or from which one or more amino acids of the naturally occurring or recombinant insulin have been added or deleted. The inhalation device according to the invention is particularly suited for the administration of vitamin A or vitamin A ester and retinoic acid or retinoic acid ester, also in combination with natural or synthetic antioxidants.